Childhood degeneration of the striatum, a region of the forebrain involved in movement, occurs in multiple disorders with devastating consequences for the patients. Infections such as streptococcus1, measles2 or herpes3, in infants can cause bilateral striatal necrosis, resulting in dystonia or dyskinesias. Juvenile Huntington?s disease (HD) also causes the atrophy of the striatum and is ultimately fatal. There is no treatment for the degeneration of the striatum, only management of some symptoms. One potential therapy for these patients is replacement of the main neuron lost in these diseases, the medium spiny neuron (MSN). Transplantation using fetal striatal progenitors has shown some promise in HD clinical trials, but there are multiple issues associated such as the need for large amounts of tissue that is not easy to obtain, issues with tissue rejection, and the ethical issues involved with using fetal cells. Preliminary studies using rodents have also shown some symptom reversal using MSNs differentiated in culture from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, these differentiations can be cost prohibitive, are largely inefficient in producing MSNs and also have incidents of graft-overgrowth. MSNs have been generated in high efficiency from transdifferentiating fibroblasts using transcription factors and microRNAs, but may have issues with epigenetic marks that reduce functionality. Published works and our preliminary studies demonstrate that less differentiated neural progenitors survive and migrate better throughout the striatum. However, transplanting cells at this stage may be problematic due to the potential of uncontrolled proliferation (tumor) or differentiation into the wrong cell types. What is needed is a way to do directed in vivo differentiations of the transplanted neural progenitors. Given these findings, we hypothesize that we can induce the expression of a combination of striatal- specific transcription factors and microRNAs, under the control of a tetracycline inducible promoter (tet-on), in iPSC-derived neural progenitors in order to rapidly accelerate the cells into MSNs. This innovative approach of transcription factor-mediated directed differentiation is an efficient way to change a cell?s fate and will allow generation of inducible MSNs for striatal transplantation replacement therapies or in vivo disease modeling. We anticipate that this study will be able to refine the process of directed differentiation human iPSCs into MSNs, laying the initial ground work for 1) generating a patient?s own tissue for autologous transplant therapy and 2) disease modeling. This proposal fulfills NINDS? mission ?to reduce the burden of neurological disease? and lead to a defined product that has inherent value to the neuroscience community.